Browsing by Subject "Graft vs Host Disease"
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Item Age is no barrier for adults undergoing HCT for AML in CR1: contemporary CIBMTR analysis(Springer Nature, 2022) Maakaron, Joseph E.; Zhang, Mei-Jie; Chen, Karen; Abhyankar, Sunil; Bhatt, Vijaya Raj; Chhabra, Saurabh; El Jurdi, Najla; Farag, Sherif S.; He, Fiona; Juckett, Mark; de Lima, Marcos; Majhail, Navneet; van der Poel, Marjolein; Saad, Ayman; Savani, Bipin; Ustun, Celalettin; Waller, Edmund K.; Litzow, Mark; Kebriaei, Partow; Hourigan, Christopher S.; Saber, Wael; Weisdorf, Daniel; Medicine, School of MedicineAcute Myeloid Leukemia (AML) has a median age at diagnosis of 67 years. The most common curative therapy remains an allogeneic hematopoietic stem cell transplantation (HCT), yet it is complicated by treatment-related mortality (TRM) and ongoing morbidity including graft versus host disease (GVHD) that may impact survival, particularly in older patients. We examined the outcomes and predictors of success in 1321 patients aged 60 years and older receiving a HCT for AML in first complete remission (CR1) from 2007-2017 and reported to the CIBMTR. Outcomes were compared in three age cohorts (60-64; 65-69; 70+). With median follow-up of nearly 3 years, patients aged 60-64 had modestly, though significantly better OS, DFS and lower TRM than those either 65-69 or 70+; cohorts with similar outcomes. Three-year OS for the 3 cohorts was 49.4%, 42.3%, and 44.7% respectively (p = 0.026). TRM was higher with increasing age, cord blood as graft source and HCT-CI score of ≥3. Conditioning intensity was not a significant predictor of OS in the 60-69 cohort with 3-year OS of 46% for RIC and 49% for MAC (p = 0.38); MAC was rarely used over age 70. There was no difference in the relapse rate, incidence of Grade III/IV acute GVHD, or moderate-severe chronic GVHD across the age cohorts. After adjusting for other predictors, age had a small effect on OS and TRM. High-risk features including poor cytogenetics and measurable residual disease (MRD) prior to HCT were each significantly associated with relapse and accounted for most of the adverse impact on OS and DFS. Age did not influence the incidence of either acute or chronic GVHD; while graft type and associated GVHD prophylaxis were most important. These data suggest that age alone is not a barrier to successful HCT for AML in CR1 and should not exclude patients from HCT. Efforts should focus on minimizing residual disease and better donor selection.Item Antigen-specific T cell responses correlate with decreased occurrence of acute GVHD in a multicenter contemporary cohort(Springer Nature, 2022) Cruz, Conrad Russell Y.; Bo, Na; Bakoyannis, Giorgos; Wright, Kaylor E.; Chorvinsky, Elizabeth A.; Powell, Allison; Bollard, Catherine M.; Jacobsohn, David; Cooke, Kenneth R.; Duncan, Christine; Krance, Robert M.; Carpenter, Paul A.; Rowan, Courtney M.; Paczesny, Sophie; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthItem Aqueous two-phase system patterning of detection antibody solutions for cross-reaction-free multiplex ELISA(Springer Nature, 2014-05-02) Frampton, John P.; White, Joshua B.; Simon, Arlyne B.; Tsuei, Michael; Paczesny, Sophie; Takayama, Shuichi; Pediatrics, School of MedicineAccurate disease diagnosis, patient stratification and biomarker validation require the analysis of multiple biomarkers. This paper describes cross-reactivity-free multiplexing of enzyme-linked immunosorbent assays (ELISAs) using aqueous two-phase systems (ATPSs) to confine detection antibodies at specific locations in fully aqueous environments. Antibody cross-reactions are eliminated because the detection antibody solutions are co-localized only to corresponding surface-immobilized capture antibody spots. This multiplexing technique is validated using plasma samples from allogeneic bone marrow recipients. Patients with acute graft versus host disease (GVHD), a common and serious condition associated with allogeneic bone marrow transplantation, display higher mean concentrations for four multiplexed biomarkers (HGF, elafin, ST2 and TNFR1) relative to healthy donors and transplant patients without GVHD. The antibody co-localization capability of this technology is particularly useful when using inherently cross-reactive reagents such as polyclonal antibodies, although monoclonal antibody cross-reactivity can also be reduced. Because ATPS-ELISA adapts readily available antibody reagents, plate materials and detection instruments, it should be easily transferable into other research and clinical settings.Item ATG5-Dependent Autophagy Uncouples T-cell Proliferative and Effector Functions and Separates Graft-versus-Host Disease from Graft-versus-Leukemia(American Association for Cancer Research, 2021) Oravecz-Wilson, Katherine; Rossi, Corinne; Zajac, Cynthia; Sun, Yaping; Li, Lu; Decoville, Thomas; Fujiwara, Hideaki; Kim, Stephanie; Peltier, Daniel; Reddy, Pavan; Medicine, School of MedicineAutophagy is a vital cellular process whose role in T immune cells is poorly understood, specifically, in its regulation of allo-immunity. Stimulation of wild-type T cells in vitro and in vivo with allo-antigens enhances autophagy. To assess the relevance of autophagy to T-cell allo-immunity, we generated T-cell-specific Atg5 knock-out mice. Deficiency of ATG5-dependent autophagy reduced T-cell proliferation and increased apoptosis following in vitro and in vivo allo-stimulation. The absence of ATG5 in allo-stimulated T cells enhanced their ability to release effector cytokines and cytotoxic functions, uncoupling their proliferation and effector functions. Absence of autophagy reduced intracellular degradation of cytotoxic enzymes such as granzyme B, thus enhancing the cytotoxicity of T cells. In several in vivo models of allo-HSCT, ATG5-dependent dissociation of T-cell functions contributed to significant reduction in graft-versus-host disease (GVHD) but retained sufficient graft versus tumor (GVT) response. Our findings demonstrate that ATG5-dependent autophagy uncouples T-cell proliferation from its effector functions and offers a potential new strategy to enhance outcomes after allo-HSCT. SIGNIFICANCE: These findings demonstrate that induction of autophagy in donor T-cell promotes GVHD, while inhibition of T-cell autophagy mitigates GVHD without substantial loss of GVL responses.Item Biomarkers for fatal immune response to stem cell treatment could reduce mortality(Taylor & Francis, 2014) Paczesny, Sophie; Pediatrics, School of MedicineItem Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease(Massachusetts Medical Society, 2021-01-07) Farag, Sherif S.; Zaid, Mohammad Abu; Schwartz, Jennifer E.; Thakrar, Teresa C.; Blakley, Ann J.; Abonour, Rafat; Robertson, Michael J.; Broxmeyer, Hal E.; Zhang, Shuhong; Medicine, School of MedicineBackground: Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known. Methods: We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation. Results: A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation. Conclusions: In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation.Item ICOSL+ plasmacytoid dendritic cells as inducer of graft-versus-host disease, responsive to a dual ICOS/CD28 antagonist(American Association for the Advancement of Science, 2020-10-07) Adom, Djamilatou; Dillon, Stacey R.; Yang, Jinfeng; Liu, Hao; Ramadan, Abdulraouf; Kushekhar, Kushi; Hund, Samantha; Albright, Amanda; Kirksey, Maykala; Adeniyan, Titilayo; Lewis, Katherine E.; Evans, Lawrence; Wu, Rebecca; Levin, Steven D.; Mudri, Sherri; Yang, Jing; Rickel, Erika; Seaberg, Michelle; Henderson, Katherine; Gudgeon, Chelsea J.; Wolfson, Martin F.; Swanson, Ryan M.; Swiderek, Kristine M.; Peng, Stanford L.; Hippen, Keli L.; Blazar, Bruce R.; Paczesny, Sophie; Pediatrics, School of MedicineAcute graft-versus-host disease (aGVHD) remains a major complication of allogeneic hematopoietic cell transplantation (HCT). CD146 and CCR5 are proteins that mark activated T helper 17 (Th17) cells. The Th17 cell phenotype is promoted by the interaction of the receptor ICOS on T cells with ICOS ligand (ICOSL) on dendritic cells (DCs). We performed multiparametric flow cytometry in a cohort of 156 HCT recipients and conducted experiments with aGVHD murine models to understand the role of ICOSL+ DCs. We observed an increased frequency of ICOSL+ plasmacytoid DCs, correlating with CD146+CCR5+ T cell frequencies, in the 64 HCT recipients with gastrointestinal aGVHD. In murine models, donor bone marrow cells from ICOSL-deficient mice compared to those from wild-type mice reduced aGVHD-related mortality. Reduced aGVHD resulted from lower intestinal infiltration of pDCs and pathogenic Th17 cells. We transplanted activated human ICOSL+ pDCs along with human peripheral blood mononuclear cells into immunocompromised mice and observed infiltration of intestinal CD146+CCR5+ T cells. We found that prophylactic administration of a dual human ICOS/CD28 antagonist (ALPN-101) prevented aGVHD in this model better than did the clinically approved belatacept (CTLA-4-Fc), which binds CD80 (B7-1) and CD86 (B7-2) and interferes with the CD28 T cell costimulatory pathway. When started at onset of aGVHD signs, ALPN-101 treatment alleviated symptoms of ongoing aGVHD and improved survival while preserving antitumoral cytotoxicity. Our data identified ICOSL+-pDCs as an aGVHD biomarker and suggest that coinhibition of the ICOSL/ICOS and B7/CD28 axes with one biologic drug may represent a therapeutic opportunity to prevent or treat aGVHD.Item Improved Reproducibility and Quality of GVHD Biomarker Assay- Application of Multiplex Microfluidic Channel System(Springer Nature, 2016) Anandi, Prathima; Tian, Xin; Chinian, Fariba; Cantilena, Caroline R.; Dunavin, Neil; Hensel, Nancy; Draper, Debbie; Koklanaris, Eleftheria; Maxwell, Sandra; Superata, Jeanine; Muranski, Pawel; Battiwalla, Minoo; Paczesny, Sophie; Barrett, A. John; Ito, Sawa; Pediatrics, School of MedicineItem Murine chronic graft-versus-host disease proteome profiling discovers CCL15 as a novel biomarker in patients(American Society of Hematology, 2018-04-12) Du, Jing; Flynn, Ryan; Paz, Katelyn; Ren, Hong-Gang; Ogata, Yuko; Zhang, Qing; Gafken, Philip R.; Storer, Barry E.; Roy, Nathan H.; Burkhardt, Janis K.; Mathews, Wendy; Tolar, Jakub; Lee, Stephanie J.; Blazar, Bruce R.; Paczesny, Sophie; Pediatrics, School of MedicineImproved diagnostic and treatment methods are needed for chronic graft-versus-host disease (cGVHD), the leading cause of late nonrelapse mortality (NRM) in long-term survivors of allogenic hematopoietic cell transplantation. Validated biomarkers that facilitate disease diagnosis and classification generally are lacking in cGVHD. Here, we conducted whole serum proteomics analysis of a well-established murine multiorgan system cGVHD model. We discovered 4 upregulated proteins during cGVHD that are targetable by genetic ablation or blocking antibodies, including the RAS and JUN kinase activator, CRKL, and CXCL7, CCL8, and CCL9 chemokines. Donor T cells lacking CRK/CRKL prevented the generation of cGVHD, germinal center reactions, and macrophage infiltration seen with wild-type T cells. Whereas antibody blockade of CCL8 or CXCL7 was ineffective in treating cGVHD, CCL9 blockade reversed cGVHD clinical manifestations, histopathological changes, and immunopathological hallmarks. Mechanistically, elevated CCL9 expression was present predominantly in vascular smooth muscle cells and uniquely seen in cGVHD mice. Plasma concentrations of CCL15, the human homolog of mouse CCL9, were elevated in a previously published cohort of 211 cGVHD patients compared with controls and associated with NRM. In a cohort of 792 patients, CCL15 measured at day +100 could not predict cGVHD occurring within the next 3 months with clinically relevant sensitivity/specificity. Our findings demonstrate for the first time the utility of preclinical proteomics screening to identify potential new targets for cGVHD and specifically CCL15 as a diagnosis marker for cGVHD. These data warrant prospective biomarker validation studies.Item Oral inflammation and microbiome dysbiosis exacerbate chronic graft-versus-host disease(American Society of Hematology, 2025) Kambara, Yui; Fujiwara, Hideaki; Yamamoto, Akira; Gotoh, Kazuyoshi; Tsuji, Shuma; Kunihiro, Mari; Oyama, Tadashi; Terao, Toshiki; Sato, Ayame; Tanaka, Takehiro; Peltier, Daniel; Seike, Keisuke; Nishimori, Hisakazu; Asada, Noboru; Ennishi, Daisuke; Fujii, Keiko; Fujii, Nobuharu; Matsuoka, Ken-Ichi; Soga, Yoshihiko; Reddy, Pavan; Maeda, Yoshinobu; Pediatrics, School of MedicineThe oral microbiota, second in abundance to the gut, is implicated in chronic systemic diseases, but its specific role in graft-versus-host disease (GVHD) pathogenesis has been unclear. Our study finds that mucositis-induced oral dysbiosis in patients after hematopoietic cell transplantation (HCT) associated with increased chronic GVHD (cGVHD), even in patients receiving posttransplant cyclophosphamide. In murine HCT models, oral dysbiosis caused by bilateral molar ligatures exacerbated cGVHD and increased bacterial load in the oral cavity and gut, with Enterococcaceae significantly increasing in both organs. In this model, the migration of Enterococcaceae to cervical lymph nodes both before and after transplantation activated antigen-presenting cells, thereby promoting the expansion of donor-derived inflammatory T cells. Based on these results, we hypothesize that pathogenic bacteria increase in the oral cavity might not only exacerbate local inflammation but also enhance systemic inflammation throughout the HCT course. Additionally, these bacteria translocated to the gut and formed ectopic colonies, further amplifying systemic inflammation. Furthermore, interventions targeting the oral microbiome mitigated murine cGVHD. Collectively, our findings highlight the importance of oral dysbiosis in cGVHD and suggest that modulation of the oral microbiome during transplantation may be an effective approach for preventing or treating cGVHD.